Adenosine is found in all living cells and can be released under appropriate conditions, such as ischemia or anoxia, where it can then act upon adenosine receptors to produce a variety of physiological effects. Adenosine receptors are now known to be integral membrane proteins which bind extracellular adenosine, thereby initiating a transmembrane signal via specific guanine nucleotide binding proteins known as G-proteins to modulate a variety of second messenger systems, including adenylyl cyclase, potassium channels, calcium channels and phospholipase C. See G. Stiles, Clin. Res. 38, 10-18 (1990); G. Stiles, J. Biol. Chem. 267, 6451-6454 (1992).
Adenosine receptors control a variety of important physiological effects including regulation of heart rate and contractility, regulation of smooth muscle tone in both blood vessels and the gastrointestinal tract, regulation of neurotransmitter release in brain, induction of sedation in the brain and regulation of platelet function. Although much biochemical and pharmacological information has become available on the two main types of adenosine receptors (known respectively as A.sub.1 and A.sub.2) which inhibit and stimulate adenylyl cyclase, much less information is available about their structure at the RNA and DNA level.
Adenosine receptors can be defined by an agonist potency series which, for the A.sub.1 receptor, is R-PIA&gt;NECA &gt;S-PIA, and which for the A.sub.2 receptor is NECA&gt;R-PIA&gt;S-PIA. See R. Olsson and J. Pearson, Physiol. Rev. 70, 761-845 (1990). Very recently we have found evidence for a unique A.sub.1 adenosine receptor which is expressed in the bovine brain which has a different potency series such that R-PIA is &gt;S-PIA which is &gt;NECA. We have cloned and sequenced this receptor and have begun studies on site-directed mutagenesis to understand the ligand binding site. See M. Olah et al., J. Biol. Chem. 267, 10764-10770 (1992). In addition, we have found a new receptor previously not suspected, which we have termed the A.sub.3 adenosine receptor. This receptor has likewise been cloned, sequenced and expressed. See F. Zhou et al., Proc. Natl. Acad. Sci. USA, in press (1992).